Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([Br:26])=[C:21]([CH3:27])[CH:20]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:6][CH:5]=1.Cl>O1CCCC1.[OH-].[Na+].C(OCC)C.O>[Br:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([S:18][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:16])([F:17])[F:15])=[CH:20][C:21]=1[CH3:27]
Reactant: COC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)O)cc2)cc(C)c1Br
Yield: 92.8 %

Procedure:
Racemic 4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoic acid methyl ester (0.424 g, 0.890 mmol) is dissolved in the tetrahydrofuran (2.5 mL) and sodium hydroxide (2.5 mL, 5N) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (2.5 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound (0.380 g, 0.826 mmol) is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:34])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH:22]5[CH2:27][CH2:26][N:25](C(=O)C(F)(F)F)[CH2:24][CH2:23]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[OH-].[K+].O>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:34])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(OC3CCN(C(=O)C(F)(F)F)CC3)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)c2cc(OC3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-6,6-dimethyl-8-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yloxy]-5,6-dihydro-benzo[b]carbazol-11-one (Compound T6-1, 28.0 mg, 52.3 μmol) was dissolved in THF (1.00 mL) and methanol (0.50 mL), added with aqueous solution of potassium hydroxide (1.00 mL, 20 wt %), and stirred at room temperature for 1 hr. The reaction solution was added to water, and extracted with mixture solution of chloroform and methanol, and dried over sodium sulfate. Then, after filtering and concentration under reduced pressure, 3-bromo-6,6-dimethyl-8-(piperidin-4-yloxy)-5,6-dihydro-benzo[b]carbazol-11-one was obtained as a crude product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=[O:3])[CH3:2].C[C:20]1(C)[CH:22]([CH:23]=[C:24]([Cl:26])[Cl:25])[CH:21]1[C:27](OCC)=O>CCO.CCO.CCO.CCO.[Ti].C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:27])[CH:22]([CH:23]=[C:24]([Cl:26])[Cl:25])[CH:2]1[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: [Ti]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 24.2 parts of m-phenoxybenzyl acetate, 28.4 parts of ethyl 2,2-dimethyl-3-(2'-,2'-dichlorovinyl)-cyclopropanecarboxylate (cis:trans ratio, 58/42) and 1.3 parts of tetraethyl titanate in 200 parts of dry toluene was stirred and heated at the boiling point. The azeotrope of ethyl acetate and toluene was removed by distillation at the rate of 50 parts per hour while maintaining the reaction volume by the addition of fresh toluene. After 4 hours 5 parts of water were added and precipitated titanium dioxide removed by filtration. The toluene was then removed by heating under reduced pressure and 0.3 mm. of mercury. Volatile fractions removed were 9.0 parts of unreacted ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)cyclopropanecarboxylate, boiling at 75°-80° and 6.3 parts of unchanged m-phenoxybenzyl acetate, boiling at 125°-135°. There was obtained 26.85 parts of m-phenoxybenzyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylate (cis trans ratio, 44/56).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.C1C=CC2[N:39]([OH:40])N=NC=2C=1.[CH3:41][C:42]1([CH3:50])[O:46][C@H:45]([CH2:47]NO)[CH2:44][O:43]1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:50][C:42]1([CH3:41])[O:46][C@@H:45]([CH2:47][O:40][NH:39][C:19]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][N:17]=[CH:16][C:15]=3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:44][O:43]1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)OC[C@@H](CNO)O1
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3sncc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]iso-thiazole-5-carboxylic acid (250 mg, 0.604 mmol), diisopropylethylamine (0.42 mL, 2.42 mmol), HOBt (163 mg, 0.1.21 mmol) and O—(((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (178 mg, 1.21 mmol) in DMF (2 mL) was added EDCI (232 mg, 1.21 mmol). The reaction mixture was stirred for 16 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 50%, EtOAc in cyclohexane) to afford the title compound as a solid (142 mg, 43%). LCMS (method B): RT=3.92 min, [M+H]+=544.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]>C(O)(C)C>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)([O:3][CH:2]([CH3:4])[CH3:1])=[O:10]
Reactant: CC(=O)Cc1ccc(C(=O)Cl)cc1
Solvent: CC(C)O
Product: CC(=O)Cc1ccc(C(=O)OC(C)C)cc1
Reaction time: 72 h

Procedure:
Isopropanol (30 ml) was added to 4-acetonylbenzoyl chloride (2.61 g) and the solution left at room temperature 3 days. Removal of the solvent gave the title compound as an oil. γ(CDCl3) 8.66 (3H, d, J=7 Hz), 7.88 (3H, s), 6.28 (2H, s), 4.78 (1H, h, J=7 Hz), 2.80 (2H, d, J=9 Hz) 2.04 (2H, d, J=9 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[CH3:16][S:17][C:18](=[N:21][C:22]#[N:23])SC>C(O)C>[C:22]([NH:21][C:18](=[N:15][CH2:14][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:10]=[CH:9][N:8]=1)[S:17][CH3:16])#[N:23]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NCCSCc1cc(CN(C)C)ccn1)NC#N
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) in ethanol (10 ml) was added over 10 minutes to a solution of dimethylcyanodithioimidocarbonate (0.71 g) in ethanol (15 ml). The solution was stirred for 30 minutes, evaporated to dryness and the residue purified by elution from a column of silica gel with 7.5% methanol/chloroform to yield N-cyano-S-methyl-N'-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethyl]-isothiourea (0.97 g) as a clear oil.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10](I)=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:26].[Na+].[OH2:31]>C(#N)C.C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:31])[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Fc1cccc2c1c(I)cn2C(c1ccccc1)c1ccccc1
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-iodo-4-fluoroindole (8.85 g, 20.7 mmol) in a mixture of acetonitrile (25 mL) and water (5 mL) was added ruthenium (III) chloride monohydrate (0.30 g, 1.45 mmol) and sodium periodate (13.3 g, 62.2 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×25 mL), saturated aqueous ammonium chloride (3×25 mL) and brine (3×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from acetonitrile to afford 1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione (1.73 g, 25%) as an orange solid: mp 168-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.49-7.41 (m, 1H), 7.38-7.28 (m, 10H), 6.86 (dd, J=8.8, 8.8 Hz, 1H), 6.80 (s, 1H), 6.45 (d, J=8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 178.3, 157.8, 157.7 (d, 1JC-F=261.0 Hz), 150.6 (d, 3JC-F=6.0 Hz), 139.7 (d, 2JC-F=10.0 Hz), 137.0, 128.5, 128.3, 127.8, 110.7 (d, 2JC-F=19.5 Hz), 108.8 (d, 4JC-F=2.9 Hz), 106.4 (d, JC-F=18.2 Hz), 28.7; MS (ES+) m/z 332.2 (M+23).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:20]([CH2:21]O)=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]>ClCCl.C(=O)([O-])O.[Na+]>[CH2:7]([C:9]1[C:20]([CH2:21][C:5]#[N:6])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: C[Si](C)(C)C#N
Reactant: CCc1nn2ccc3c(c2c1CO)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn2ccc3c(c2c1CC#N)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (836 μL, 6.60 mmol) and trimethylsilyl cyanide (1.17 mL, 8.77 mmol) in dichloromethane (5 mL) was added a solution of (2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (480 mg, 2.20 mmol) in dichloromethane (10 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (296 mg, yield 59%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[C:14]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[C:19]=1[NH:28]C(=O)OC(C)(C)C)([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[NH2:28][C:19]1[C:20]([O:26][CH3:27])=[N:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(OC)nc(OC)c1NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(OC)nc(OC)c1N
Temperature: 25 °C
Yield: 97 %

Procedure:
p-Toluene sulfonic acid hydrate (0.282 g, 1.48 mmol) was dissolved in toluene (11 mL) and heated to reflux overnight with azeotropic removal of H2O (Dean-Stark trap). The next day, the reaction was cooled to room temperature and the product of Example 28, dissolved in toluene (4 mL), was added. The reaction was heated back to reflux for 0.5 hours. The reaction was cooled to room temperature and poured into NaHCO3 (sat) and extracted 3 times with ether. The organics were combined, washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography using hexane/ethyl acetate as eluant (gradient 100% to 9/1) to provide 0.278 g (97%) of methyl 3-amino-2,6-dimethoxyisonicotinate as a yellow solid. Electrospray Mass Spec: 212.8 (M+H)+
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.295 g, 1.1 mmol), tetrakis(triphenyl-phosphine)palladium (0.058 g, 0.044 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (384 mg, 59%). MS (ISP) 590.4 [(M+H)+]; mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8](SC)[N:7]=1.O[O:20][S:21]([O-:23])=O.[K+].S(=O)(O)[O-].[Na+].[CH3:30]O>O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[C:8]([S:21]([CH3:30])(=[O:23])=[O:20])[N:7]=1
Reactant: CSc1ncc(F)c(NCc2ccccc2F)n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ncc(F)c(NCc2ccccc2F)n1
Temperature: 10 °C
Yield: 85 %

Procedure:
To a solution of (2-fluorobenzyl)-(5-fluoro-2-methylsulfanylpyrimidin-4-yl)amine (2.10 g, 7.86 mmol) in MeOH (26 mL) was added a solution of OXONE™ (10.14 g, 16.5 mmol) in H2O (52 mL) dropwise over a 20 min period at −45° C., and the resulting mixture was slowly warmed to 10° C. over a period of 14 h. The mixture was treated with sodium bisulfite (−3 g) and the majority of the MeOH was removed on the rotary evaporator. The aqueous residue was extracted with EtOAc (3×150 mL), and the organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give a peach solid. The solid was purified by flash chromatography (40 g SiO2; 0→100% EtOAc/hexanes) to give 2-fluorobenzyl-(5-fluoro-2-methanesulfonylpyrimidin-4-yl)amine (1.99 g, 85%) as a white solid: mp 105-107° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.9 Hz, 1H), 7.46 (td, J=7.6, 1.7 Hz, 1H), 7.31 (m, 1H), 7.14 (td, J=7.5, 1.1 Hz, 1H), 7.08 (m, 1H), 5.89 (s, 1H), 4.82 (d, J=6.0 Hz, 2H), 3.25 (s, 3H); CIMS m/z 299 ([M]+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]1=2>[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Product: CN(C)CCN1CCOc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (210 mg, 0.836 mmol) and Pd—C (10% wt, 89 mg, 0.084 mmol) in dry EtOH (15 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 3 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a Celite pad and washed with EtOH (15 mL). The light purple filtrate was concentrated to give crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine. A solution of this crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (185 mg, 0.836 mmol) in dry EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (477 mg, 1.672 mmol) and stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2, followed by 5:95 (2M NH3 in MeOH):CH2Cl2, to give a yellow solid (150 mg, 54%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=3.6, 0.9 Hz, 1H), 7.56 (dd, J=5.1, 0.9 Hz, 1′-1), 7.07 (dd, J=5.1, 3.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35-6.26 (m, 4H), 4.14 (t, J=3.9 Hz, 2H), 3.33-3.29 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.19 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (25); ESI-HRMS calculated for C17H23N4OS (MH+): 331.1587, Observed: 331.1594; HPLC purity: 99.0% by area.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(Cl)cc(I)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1c(Cl)cc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-iodoaniline (10.4 g, 36.0 mmol) is dissolved in toluene (100 mL) and treated with 1.5 equivalents of phenylboronic acid (6.6 g, 54 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in ethanol (20 mL). Sodium carbonate (40 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature, the mixture is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-phenylaniline (m.p. 112–113° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:16]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: c1cc(-c2ccnc3ccnn23)ccn1
Reactant: Cln1nnc2ccccc21
Solvent: ClCCl
Product: Clc1cnn2c(-c3ccncc3)ccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.01 mole of 7-(4-pyridyl)pyrazolo[1,5-a]pyrimidine in cold dichloromethane is added 0.011 mole of N-chlorobenzotriazole. The mixture is stirred at room temperature for one hour and heated on a steam bath for 15 minutes. The product is worked up as for Example 62 to give the product of the example, m.p. 183°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][CH3:12])=[CH:9][N:10]=1)[C:5]([OH:7])=O.ClC1[CH:15]=[C:16](C(NC)=CN=1)[C:17]([O:19][CH3:20])=[O:18].[OH-:26].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][N:10]=1)[N:11]([CH3:12])[C:15](=[O:26])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:5]2[OH:7]
Reactant: CNc1cnc(Cl)cc1C(=O)OC
Reactant: CNc1cnc(Cl)cc1C(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(O)c2cc(Cl)ncc2n(C)c1=O
Temperature: 55 °C

Procedure:
2-Chloro-5-(methylamino)isonicotinic acid. A mixture of methyl 2-chloro-5-(methylamino)isonicotinate (10 g, 0.05 mol) and 2 N NaOH (50 mL) in EtOH (50 mL) was heated at 55° C. for 2 hours. The reaction mixture was cooled to room temperature and most of the EtOH was evaporated under reduced pressure. The pH of the aqueous residue was adjusted to pH=3 with 1 N HCl, and the solid precipitate was filtered and dried in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.85 mmol, 1.0 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (250 mg, 1.0 mmol, 1.2 equiv.), Pd(dippf)Cl2 (69.5 mg, 0.085 mmol, 0.1 equiv.), Na2CO3 (360.4 mg, 3.4 mmol, 4.0 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 60:1) to afford title compound 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl)acetonitrile (Compound 17) (28.6 mg, 10%) as solid. LC-MS (m/z)=317.1 [M+H]+;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].CCOC(C)=O.O>CN(C=O)C>[C:15]([O:14][C:12]([N:10]1[CH2:9][CH2:8][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:28][CH2:27][CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[C:5]=2[CH2:11]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)nc(Cl)c2C1
Reactant: NCCc1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Cl)nc(NCCc3ccccn3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (100 mg, 0.329 mmol) and TEA (0.137 mL, 0.986 mmol) in DMF (1.5 mL) was treated with 2-(2-pyridyl)ethyl amine (40.2 mg, 0.329 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was EtOAc (10 mL) and H2O (10 mL), and extracted with EtOAc (2×10 mL). The combined organic phases were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes to afford the title compound as a pale yellow gum (96 mg, 75%). Data for G-1: 1H NMR (500 MHz, CDCl3) δ 8.524-8.64 (br m, 1H), 7.61-7.69 (br m, 1H), 7.15-7.24 (m, 2H), 6.67-6.89 (br m, 1H), 4.24 (s, 2H), 3.67 (br m, 2H), 3.08 (t, J=9.0 Hz, 2H), 2.75 (br s, 2H), 1.51 (s, 9H); LC/MS: rt=1.35 min, m/z (M+H)=390.1 found; 390.2 calcd.